WO2005074387A2 - Nouvelles formes cristallines d'hydrochlorure de 4-[2-di-n-propylamino)ethyl]-2 (3h)- indolone - Google Patents

Nouvelles formes cristallines d'hydrochlorure de 4-[2-di-n-propylamino)ethyl]-2 (3h)- indolone Download PDF

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Publication number
WO2005074387A2
WO2005074387A2 PCT/IN2004/000439 IN2004000439W WO2005074387A2 WO 2005074387 A2 WO2005074387 A2 WO 2005074387A2 IN 2004000439 W IN2004000439 W IN 2004000439W WO 2005074387 A2 WO2005074387 A2 WO 2005074387A2
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WIPO (PCT)
Prior art keywords
propylamino
ethyl
indolone
solvent
hydrochloride
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PCT/IN2004/000439
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English (en)
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WO2005074387A3 (fr
Inventor
Hetalkumar Virendrabhai Patel
Jitendra Gopaldas Dipchandani
Raja Jyotir Jani
Rajamannar Thennati
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Sun Pharmaceutical Industries Limited
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Application filed by Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2005074387A2 publication Critical patent/WO2005074387A2/fr
Publication of WO2005074387A3 publication Critical patent/WO2005074387A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the present invention relates to novel crystal forms of 4-[2-(di-n-propylamino)ethyl] 2(3 H)- indolone hydrochloride, compound of formula I, commonly known as ropinirole hydrochloride (INN Name) used for the treatment of Parkinson's disease.
  • United States patent number 4,452,808 (Assigned to SmithKline Beecham Company, referred to herein as '808) discloses compound of formula I and the process of its preparation. Subsequently other patents viz. United States patent number 4,950,765; United States patent number 4,997,954, United States patent number 5,336,781 (referred to herein as '781) and PCT publication number 94/15918 (All Assigned to SmithKline) describe various synthetic routes tor preparing compound of formula I. These patents/publications do not disclose any crystalline forms of 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride. We have now found novel crystal forms of 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of formula I.
  • the object of the present invention is to provide novel crystal forms of 4-[2-(di-n- propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of formula I.
  • Yet another object is to provide process for the preparation of novel crystal forms of 4-[2-(di-n- propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of formula I.
  • the present invention provides a simple and viable process for the preparation of new crystal forms of Ropinirole hydrochloride, 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride, compound of formula I.
  • novel crystal forms I and II are characterized by x-ray powder diffractograms as represented in figs 1 & 2.
  • the novel crystal form I exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in d spacing values at about 12.33, 11.98, 8.88, 7.73, 6.59, 6.01, 5.76, 5.38, 5.08, 4.83, 4.61, 4.37, 4.18, 3.99, 3.96, 3.93, 3.90, 3.75, 3.61, 3.54, 3.43, 3.39, 3.32, 3.29, 3.22, 3.12, 2.96, 2.90, 2.83, 2.81, 2.70, 2.64, 2.53, 2.48, 2.42, 2.37, 2.35, 2.30 ⁇ 0.2 A.
  • the novel crystal form I exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 7.16, 7.36, 9.94, 11.43,13.42, 14.70, 15.36, 16.44, 17.43, 18.33,19.22, 20.27, 21.19, 22.21, 22.41, 22.59, 22.75, 23.66, 24.58, 25.13, 25.93, 26.26, 26.75, 27.03, 27.61, 28.49, 30.06, 30.76, 31.48, 31.80, 33.10, 33.82, 35.33, 36.11, 37.04, 37.93, 38.26, 38.98 ⁇ 0.2.
  • the novel crystal form II exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in d spacing values at about 11.81, 8.70, 7.65, 6.53, 5.96, 5.70, 5.35, 5.04, 4.78, 4.58, 4.34, 4.15, 3.98, 3.90, 3.73, 3.58, 3.51, 3.41, 3.31,3.28, 3.21, 3.09, 3.01, 2.99, 2.95, 2.92, 2.88, 2.80, 2.69, 2.52, 2.46, 2.44, 2.41, 2.34, 2.30 ⁇ 0.2 A.
  • the novel crystal form II exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 7.47, 10.14,11.54,13.53, 14.83, 15.52, 16.54, 17.55, 18.53, 19.35, 20.42, 21.32, 22.31, 22.74, 23.82, 24.82, 25.31, 26.04, 26.87, 27.14, 27.72, 28.81, 29.55, 29.85, 30.22, 30.55, 31.02, 31.91, 33.21, 35.48, 36.39, 36.70, 37.22, 38.33, 39.06 ⁇ 0.2 .
  • novel crystal forms have also been characterized by crystal parameters such as particle size, aspect ratio.
  • novel crystal forms of 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride, compound of formula I may be prepared by different methods such as A. Process comprising a. dissolving 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride in solvent; b. cooling followed by optional partial or complete removal of said solvent.
  • B. Process comprising a. dissolving 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone in solvent; b. adding ammonia; c. optionally extracting with anti-solvent; and d. adding alkartolic hydrochloric acid for crystallizing.
  • 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride may be dissolved in solvent(s) followed by crystallizing 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride from the solvent(s). Crystallization may be achieved by dissolving 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride in a solvent followed by cooling or by addition of anti-solvent or by distilling off the solvent in the presence or absence of vacuum.
  • the solvent(s) for crystallization may be selected from the group consisting of aliphatic or aromatic or cyclic hydrocarbon such as n-pentane, n-hexane, n-octane, cyclohexane, toluene and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, chlorobenzene and the like; alkanols such as methanol, ethanol, t-butanol, isopropanol, cyclohexanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like; ketones such as acetone, methylethylketone, cyclohexanone and the like; nitriles such as acetonitrile and the like; amides such as dimethylformamide, dimethylacetamide and the like; esters such as ethylacetate, butylacetate and
  • the 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride may be taken in water or water admixed with water miscible organic solvent.
  • the aqueous phase may be treated with a base, followed by extraction with water immiscible organic solvent or mixture of water immiscible organic solvent with polar solvent(s), to get 4-[2-(di-n-propylamino)ethyl]-2(3H)- indolone as a free base in solvent.
  • the hydrochloride salt formation may be carried out by adding hydrochloric acid which is dissolved in organic solvent or by passing HC1 gas to precipitate 4-[2- (Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride .
  • the base may be selected from organic base such as ammonia, primary, secondary or tertiary amine bases and the like or inorganic base such as salts of alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates and the like.
  • the base may be used as such or as a solution in water or water miscible solvent
  • the addition of base may be carried at a temperature ranging from about 0 to 120°C.
  • the base is ammonia. Ammonia may be used in gaseous form or as an aqueous solution.
  • Extraction of the 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone free base may be carried out with water immiscible organic solvents like aliphatic or aromatic hydrocarbons such as n- pentane, n-hexane, n-octane, cyclohexane, toluene and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like; esters such as ethylacetate, butylacetate and the like; or mixture of these solvents with alkanol like methanol, ethanol, isopropanol and the like, preferably with hydrocarbons .
  • water immiscible organic solvents like aliphatic or aromatic hydrocarbons such as n- pentane, n-hexane, n-octane, cyclohexane, toluene and the like
  • the hydrochloride salt formation may be carried out with hydrochloric acid dissolved in alcoholic solvent like methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol, isobutanol or by passing HC1 gas at a temperature ranging from about -10 to 100°C to get 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride.
  • alcoholic solvent like methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol, isobutanol or by passing HC1 gas at a temperature ranging from about -10 to 100°C to get 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride.
  • Crystallization of 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride obtained by any of these methods may be carried out at ambient or lower temperatures.
  • the process of crystallization may be carried out with or without the presence of seed crystals.
  • Crystallization may be allowed to occur by chilling or seeding or scratching the glass of the reaction vessel or cooling and other such common techniques.
  • Isolation of the novel crystal forms may be achieved by using standard techniques known to those skilled in the art such as filtration/centrifugation and drying. Filtration may be carried out in the presence or absence of vacuum. Drying may be carried out at ambient or elevated temperature in the presence or absence of vacuum.
  • the product may be dried using different techniques of drying like fluid bed drying, tray drying, spray freeze drying and rotatory drying techniques with or without application of vacuum and / or under inert conditions.
  • Example 2 Preparation of crystal form II of 4-[2-(Di-n-propylamino)ethyI]-2(3H)-indoIone hydrochloride To the solution 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride (7.0 gm) in water (42.0 ml), was added at 22 to 25° C temperature, 25 % aqueous Ammonia solution (4.0 ml) and stirred for 30 minutes. Add to the aqueous layer Toluene (28.0 ml) and extract base in Toluene.
  • the product exhibited DSC (Diffraction scanning calorimetry) of 246.39°C.
  • Form II is analysed for particle size and aspect ratio and found to be as follows:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à de nouvelles formes cristallines d'hydrochlorure de 4-[2-di-n-propylamino)éthyl]-2 (3h)- indolone ainsi qu'au procédé permettant leur préparation.
PCT/IN2004/000439 2003-12-30 2004-12-30 Nouvelles formes cristallines d'hydrochlorure de 4-[2-di-n-propylamino)ethyl]-2 (3h)- indolone WO2005074387A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1327/MUM/2003 2003-12-30
IN1327MU2003 2003-12-30

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WO2005074387A2 true WO2005074387A2 (fr) 2005-08-18
WO2005074387A3 WO2005074387A3 (fr) 2005-10-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105061291A (zh) * 2015-09-08 2015-11-18 张涛 一种杂稠环取代的吲哚酮类化合物的合成方法
CN105061290A (zh) * 2015-08-28 2015-11-18 张文莲 一种吲哚酮类化合物的合成方法
CN115466209A (zh) * 2022-09-29 2022-12-13 南通大学 一种罗匹尼罗环戊烷并吲哚酮杂质的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452808A (en) * 1982-12-07 1984-06-05 Smithkline Beckman Corporation 4-Aminoalkyl-2(3H)-indolones
US4950765A (en) * 1986-08-30 1990-08-21 Smith Kline & French Laboratories Limited Process
US4997954A (en) * 1987-06-19 1991-03-05 Smith Kline & French Laboratories Limited Process for preparing substituted isoindolinone derivatives
WO1994015918A1 (fr) * 1993-01-08 1994-07-21 Smithkline Beecham Plc Procede de preparation de derives de l'indolone substitues
US5336781A (en) * 1990-04-17 1994-08-09 Smithkline & French Laboratories Limited Process

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452808A (en) * 1982-12-07 1984-06-05 Smithkline Beckman Corporation 4-Aminoalkyl-2(3H)-indolones
US4950765A (en) * 1986-08-30 1990-08-21 Smith Kline & French Laboratories Limited Process
US4997954A (en) * 1987-06-19 1991-03-05 Smith Kline & French Laboratories Limited Process for preparing substituted isoindolinone derivatives
US5336781A (en) * 1990-04-17 1994-08-09 Smithkline & French Laboratories Limited Process
WO1994015918A1 (fr) * 1993-01-08 1994-07-21 Smithkline Beecham Plc Procede de preparation de derives de l'indolone substitues

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105061290A (zh) * 2015-08-28 2015-11-18 张文莲 一种吲哚酮类化合物的合成方法
CN105061291A (zh) * 2015-09-08 2015-11-18 张涛 一种杂稠环取代的吲哚酮类化合物的合成方法
CN105061291B (zh) * 2015-09-08 2017-08-04 江俞 一种杂稠环取代的吲哚酮类化合物的合成方法
CN115466209A (zh) * 2022-09-29 2022-12-13 南通大学 一种罗匹尼罗环戊烷并吲哚酮杂质的合成方法

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